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A new antibiotic selectively kills Gram-negative pathogens

Author

Listed:
  • Yu Imai

    (Northeastern University)

  • Kirsten J. Meyer

    (Northeastern University)

  • Akira Iinishi

    (Northeastern University)

  • Quentin Favre-Godal

    (Northeastern University)

  • Robert Green

    (Northeastern University)

  • Sylvie Manuse

    (Northeastern University)

  • Mariaelena Caboni

    (Northeastern University)

  • Miho Mori

    (Northeastern University)

  • Samantha Niles

    (Northeastern University)

  • Meghan Ghiglieri

    (Northeastern University)

  • Chandrashekhar Honrao

    (Northeastern University)

  • Xiaoyu Ma

    (Northeastern University)

  • Jason J. Guo

    (Northeastern University
    Northeastern University)

  • Alexandros Makriyannis

    (Northeastern University)

  • Luis Linares-Otoya

    (Justus-Liebig-University of Giessen)

  • Nils Böhringer

    (Justus-Liebig-University of Giessen)

  • Zerlina G. Wuisan

    (Justus-Liebig-University of Giessen)

  • Hundeep Kaur

    (University of Basel)

  • Runrun Wu

    (Purdue University
    Purdue University)

  • André Mateus

    (European Molecular Biology Laboratory)

  • Athanasios Typas

    (European Molecular Biology Laboratory)

  • Mikhail M. Savitski

    (European Molecular Biology Laboratory)

  • Josh L. Espinoza

    (J. Craig Venter Institute
    J. Craig Venter Institute)

  • Aubrie O’Rourke

    (J. Craig Venter Institute
    J. Craig Venter Institute)

  • Karen E. Nelson

    (J. Craig Venter Institute
    J. Craig Venter Institute
    J. Craig Venter Institute
    J. Craig Venter Institute)

  • Sebastian Hiller

    (University of Basel)

  • Nicholas Noinaj

    (Purdue University
    Purdue University)

  • Till F. Schäberle

    (Justus-Liebig-University of Giessen
    Fraunhofer Institute for Molecular Biology and Applied Ecology
    Partner Site Giessen-Marburg-Langen)

  • Anthony D’Onofrio

    (Northeastern University)

  • Kim Lewis

    (Northeastern University)

Abstract

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds3,4. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s2. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.

Suggested Citation

  • Yu Imai & Kirsten J. Meyer & Akira Iinishi & Quentin Favre-Godal & Robert Green & Sylvie Manuse & Mariaelena Caboni & Miho Mori & Samantha Niles & Meghan Ghiglieri & Chandrashekhar Honrao & Xiaoyu Ma , 2019. "A new antibiotic selectively kills Gram-negative pathogens," Nature, Nature, vol. 576(7787), pages 459-464, December.
  • Handle: RePEc:nat:nature:v:576:y:2019:i:7787:d:10.1038_s41586-019-1791-1
    DOI: 10.1038/s41586-019-1791-1
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    Citations

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    Cited by:

    1. Runrun Wu & Jeremy W. Bakelar & Karl Lundquist & Zijian Zhang & Katie M. Kuo & David Ryoo & Yui Tik Pang & Chen Sun & Tommi White & Thomas Klose & Wen Jiang & James C. Gumbart & Nicholas Noinaj, 2021. "Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Xu Wang & Sarah B. Nyenhuis & Harris D. Bernstein, 2024. "The translocation assembly module (TAM) catalyzes the assembly of bacterial outer membrane proteins in vitro," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Zhuo Cheng & Bei-Bei He & Kangfan Lei & Ying Gao & Yuqi Shi & Zheng Zhong & Hongyan Liu & Runze Liu & Haili Zhang & Song Wu & Wenxuan Zhang & Xiaoyu Tang & Yong-Xin Li, 2024. "Rule-based omics mining reveals antimicrobial macrocyclic peptides against drug-resistant clinical isolates," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Shan Wang & Sixing Lin & Qing Fang & Roland Gyampoh & Zhou Lu & Yingli Gao & David J. Clarke & Kewen Wu & Laurent Trembleau & Yi Yu & Kwaku Kyeremeh & Bruce F. Milne & Jioji Tabudravu & Hai Deng, 2022. "A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Yunmin Yang & Binbin Chu & Jiayi Cheng & Jiali Tang & Bin Song & Houyu Wang & Yao He, 2022. "Bacteria eat nanoprobes for aggregation-enhanced imaging and killing diverse microorganisms," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Zhenyan Zhang & Qi Zhang & Tingzhang Wang & Nuohan Xu & Tao Lu & Wenjie Hong & Josep Penuelas & Michael Gillings & Meixia Wang & Wenwen Gao & Haifeng Qian, 2022. "Assessment of global health risk of antibiotic resistance genes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Sijia Guo & Shu Wang & Suze Ma & Zixin Deng & Wei Ding & Qi Zhang, 2022. "Radical SAM-dependent ether crosslink in daropeptide biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    8. Ruihuan Yang & Qing Shi & Tingting Huang & Yichao Yan & Shengzhang Li & Yuan Fang & Ying Li & Linlin Liu & Longyu Liu & Xiaozheng Wang & Yongzheng Peng & Jiangbo Fan & Lifang Zou & Shuangjun Lin & Gon, 2023. "The natural pyrazolotriazine pseudoiodinine from Pseudomonas mosselii 923 inhibits plant bacterial and fungal pathogens," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Chih-Wei Chen & Nadja Leimer & Egor A. Syroegin & Clémence Dunand & Zackery P. Bulman & Kim Lewis & Yury S. Polikanov & Maxim S. Svetlov, 2023. "Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Katherine L. Fenn & Jim E. Horne & Joel A. Crossley & Nils Böhringer & Romany J. Horne & Till F. Schäberle & Antonio N. Calabrese & Sheena E. Radford & Neil A. Ranson, 2024. "Outer membrane protein assembly mediated by BAM-SurA complexes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Christopher Jonkergouw & Ngong Kodiah Beyeh & Ekaterina Osmekhina & Katarzyna Leskinen & S. Maryamdokht Taimoory & Dmitrii Fedorov & Eduardo Anaya-Plaza & Mauri A. Kostiainen & John F. Trant & Robin H, 2023. "Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    12. Ana Teresa López-Jiménez & Serge Mostowy, 2021. "Emerging technologies and infection models in cellular microbiology," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    13. Yuqing Li & Yeying Ma & Yinzheng Xia & Tao Zhang & Shuaishuai Sun & Jiangtao Gao & Hongwei Yao & Huan Wang, 2023. "Discovery and biosynthesis of tricyclic copper-binding ribosomal peptides containing histidine-to-butyrine crosslinks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    14. Parthasarathi Rath & Adrian Hermann & Ramona Schaefer & Elia Agustoni & Jean-Marie Vonach & Martin Siegrist & Christian Miscenic & Andreas Tschumi & Doris Roth & Christoph Bieniossek & Sebastian Hille, 2023. "High-throughput screening of BAM inhibitors in native membrane environment," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    15. Bob Schiffrin & Joel A. Crossley & Martin Walko & Jonathan M. Machin & G. Nasir Khan & Iain W. Manfield & Andrew J. Wilson & David J. Brockwell & Tomas Fessl & Antonio N. Calabrese & Sheena E. Radford, 2024. "Dual client binding sites in the ATP-independent chaperone SurA," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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